• Acute myeloid leukemia (AML) patients present an altered glucose metabolism signature.• A panel of 6 metabolite biomarkers involved in glucose metabolism are identified with prognostic value for cytogenetically normal AML.Acute myeloid leukemia (AML) is a group of hematological malignancies with high heterogeneity. There is an increasing need to improve the risk stratification of AML patients, including those with normal cytogenetics, using molecular biomarkers. Here, we report a metabolomics study that identified a distinct glucose metabolism signature with 400 AML patients and 446 healthy controls. The glucose metabolism signature comprises a panel of 6 serum metabolite markers, which demonstrated prognostic value in cytogenetically normal AML patients. We generated a prognosis risk score (PRS) with 6 metabolite markers for each patient using principal component analysis. A low PRS was able to predict patients with poor survival independently of wellestablished markers. We further compared the gene expression patterns of AML blast cells between low and high PRS groups, which correlated well to the metabolic pathways involving the 6 metabolite markers, with enhanced glycolysis and trichloracetic acid cycle at gene expression level in low PRS group. In vitro results demonstrated enhanced glycolysis contributed to decreased sensitivity to antileukemic agent arabinofuranosyl cytidine (Ara-C), whereas inhibition of glycolysis suppressed AML cell proliferation and potentiated cytotoxicity of Ara-C. Our study provides strong evidence for the use of serum metabolites and metabolic pathways as novel prognostic markers and potential therapeutic targets for AML. (Blood. 2014;124(10):1645-1654

Acute myeloid leukemia (AML) is a life-threatening hematological disease. Novel diagnostic and prognostic markers will be essential for new therapeutics and for significantly improving the disease prognosis. To characterize the metabolic features associated with AML and search for potential diagnostic and prognostic methods, here we analyzed the phenotypic characteristics of serum metabolite composition (metabonome) in a cohort of 183 patients with de novo acute myeloid leukemia together with 232 age- and gender-matched healthy controls using (1)H NMR spectroscopy in conjunction with multivariate data analysis. We observed significant serum metabonomic differences between AML patients and healthy controls and between AML patients with favorable and intermediate cytogenetic risks. Such differences were highlighted by systems differentiations in multiple metabolic pathways including glycolysis/gluconeogenesis, TCA cycle, biosynthesis of proteins and lipoproteins, and metabolism of fatty acids and cell membrane components, especially choline and its phosphorylated derivatives. This demonstrated the NMR-based metabonomics as a rapid and less invasive method for potential AML diagnosis and prognosis. The serum metabolic phenotypes observed here indicated that integration of metabonomics with other techniques will be useful for better understanding the biochemistry of pathogenesis and progression of leukemia.

Abstract:An optimized method based on GC-MS with ethyl chloroformate derivatization has been developed for the comprehensive analysis of endogenous metabolites in serum. Twenty-two reference standards and serum samples were used to validate the proposed method. The correlation coefficient was higher than 0.9900 for each of the standards, and the LOD varied from 125 to 300 pg on-column. The analytical equipment exhibited good repeatability (RSD<10%) for all of the standards. Both the repeatability and the within-48-h stability of the analytical method were satisfactory (RSD<10%) for the 18 metabolites identified in the serum samples. Mean recovery was acceptable for the 18 metabolites, ranging from 70% to 120% with RSDs of less than 10%. Using the optimized protocol and a subsequent multivariate statistical technique, complete differentiation was achieved between the metabolic profile of uremic patients and that of age-and sex-matched normal subjects. Significantly decreased levels of valine, leucine, and isoleucine and increased levels of myristic acid and linoleic acid were observed in the patient group. This work demonstrated that this method is suitable for serumbased metabolic profiling studies.

Osteosarcoma (OS) is the most common malignant bone tumor found in children. Currently, researchers have focused on protein and gene levels, while the associated metabolic variations have been poorly understood. In this study, we used a gas chromatography mass spectrometry approach and profiled small-molecule metabolites in serum and urine of 24 OS patients, 19 benign bone tumor patients, and 32 healthy controls, to determine whether there are significant alterations associated with carcinogenesis. The metabonomic results demonstrate clear intergroup separations between healthy control subjects and bone tumor patients in the orthogonal partial least-squares-discriminant analysis (OPLS-DA) models. Differential metabolites identified from the metabonomic analysis suggest a disrupted energy metabolism in OS patients, as characterized by significantly down-regulated TCA cycle and glycolysis, down-regulated lipid metabolism, dysregulated sugar levels, and up-regulated amino acid metabolism. Additionally, an increased activity of glutathione metabolism, and increased polyamine metabolism also contributed to a characteristic metabolic signature of OS patients.

Life science and biotechnology have become a top priority in research and development in many countries as the world marches into the new century. China as a developing country with a 1.3 billion population and booming economy is actively meeting the challenge of a new era in this area of research. Owing to support from the government and the scientific community, and reform to improve the infrastructure, recent years have witnessed a rapid progress in some important fields of life science and biotechnology in China, such as genomics and protein sciences, neuroscience, systematics, super-hybrid rice research, stem cell and cloning technology, gene therapy and drug/vaccine development. The planned expansion and development of innovation in related sectors and the area of bioethics are described and discussed.

Modern life sciences have been introduced into China from the West for more than 170 years; however, the fast progress was only seen in the past three decades. How China feeds its people and keeps them healthy remains a mystery for many Westerners. Chinese life scientists have done their best to increase the yields of rice and other crops, and develop vaccines and treatments to combat the major diseases in China. Thanks to the fast growing economy, the Chinese government input in research and development was significantly increased and led to the great leap forward of life sciences in the past 30 years. The stories behind the past and present life sciences in China are permeated with legends, and they are worthwhile knowing. Key Concepts Life sciences in China are mainly supported by the government. The Chinese government looks at life sciences as the driving force for sustainable economic growth. Feeding the huge population and keeping the people healthy are the main challenges faced by Chinese life scientists. The leap forward of genomics and the significant increase of government input led to the fast progress of life sciences in China. Stem cell research and neuroscience are the fastest growing fields in China.